Cadherin-mediated adhesion results in the formation of highly organized adherens junctions, the key structures for a variety of morphogenetic processes. Our experiments show that cadherin-mediated adhesion is based on the equilibrium between formation and disintegration of cadherin adhesive dimers. These dynamics are mediated by an active process that continuously removes cadherin molecules from the junction. We propose that these two processes-cadherin dimer assembly and disassembly- control the strength and plasticity of intercellular contacts. Our grant centers around two topics: the mechanisms of cadherin adhesive dimer clustering and the mechanisms of cadherin dynamics in adherens junctions. Our preliminary experiments suggest that cadherin clustering is a diffusion-trap process that is negatively regulated by diverse mechanisms, one of which is cadherin endocytosis. The exact mechanisms regulating cadherin clustering and the functional significance of these mechanisms during skin development in early Xenopus embryogenesis and human keratinocyte stratification are addressed in Specific Aim 1. The elucidation of the detailed parameters and molecular aspects of cadherin dynamics in adherens junctions is described in Specific Aim 2. Finally, the conformational changes in the cadherin/catenin complex that could regulate cadherin dynamics are the focus of Specific Aim 3. The completion of this project will allow us to design specific animal experiments and clinical studies aimed at understanding the role of cadherin adhesion in complex normal and pathological processes such as wound healing and lymphocyte epidermal infiltration. The proposed work is also a critical step toward the development of synthetic adhesion modulators and their application in medicine. PUBLIC HEALTH RELEVANCE: Our preliminary studies show that two processes-cadherin dimer assembly and disassembly- control the strength and plasticity of intercellular contacts. Experiments designed in this proposal will uncover detailed mechanisms of these two crucial processes. The completion of this research will allow us to design animal experiments and clinical studies aimed at understanding the role of cadherin adhesion in wound healing and pathological morphogenesis, such as lymphocyte epidermal infiltration. The work will make a significant impact in other fields, because cadherin adhesion is a basic process that organizes virtually all human tissues. The study is also a critical step toward the development of synthetic adhesion modulators and their application in medicine.